Long term goals of our lab are to better understand the biological actions of vitamin E compounds at the cellular and molecular levels in normal and cancerous states. Studies in our lab show that a succinate derivative of natural vitamin E (RRR-alpha-tocopherol) referred to as vitamin E succinate (RRR-alpha-tocopheryl succinate; VES) is capable of inhibiting the proliferation of human breast cancer cells in culture. Previous studies by our lab demonstrating that VES inhibits the proliferation of human breast cancer cells by the induction of autocrine acting growth- inhibitory factors, one of which is tumor growth factor-beta (TGF-beta), represent a major conceptual advance in the understanding of growth regulation by vitamin E compounds. Proposed studies will use estrogen receptor-positive (ER+) and estrogen receptor negative (ER-) human breast cancer cells as experimental models to further investigate the mechanisms whereby VES is causing growth inhibition. Specific objectives are to characterize the connection between VES's ability to inhibit human breast cancer cell proliferation and its effects on the expression of TGF-beta subtype expression and activation and TGF-beta receptor expression. The proposed studies will increase basic knowledge about biological actions of VES and will document how VES is inducing the secretion of biologically active TGF- betas by breast cancer cells and how VES is enhancing the growth inhibitory actions of exogenous TGF-betas on breast cancer cell proliferation. These studies are critical for generating important information that will be useful in designing in vivo studies for testing the potential chemopreventative and chemotherapeutic use of VES in treatment of human breast cancer.